Implantable Drug Delivery Devices for Localized Drug Delivery

ABSTRACT

Provided herein are drug implants comprising a therapeutically active agent for the treatment of disease in a subject. In some cases, the drug implant may comprise a polymer matrix and a therapeutically active agent disposed therein. Additionally provided are methods for manufacturing the drug implants and methods of treating diseases with the implants. In some cases, the drug implant may comprise bicalutamide, e.g., for use in the treatment of prostate cancer.

BACKGROUND OF THE DISCLOSURE

The burden of suffering from prostate cancer in the United States issignificant. In 2009, approximately 192,000 men were diagnosed withprostate cancer, and 27,000 men were expected to die from this disease.Approximately 2.2 million living American men have been diagnosed withprostate cancer, and some are living with metastatic disease, a painfuland functionally limiting stage of the disease. Prostate cancer is byfar the most commonly diagnosed cancer among American men and remainsthe second leading cause of cancer death in men. Hormonal therapy ofprostate cancer includes a wide variety of treatments designed to affectcells whose normal functioning depends on androgens, which includetestosterone and dihydrotestosterone, among others. Prostate cancercells are generally very susceptible to treatments that lower androgenlevels or affect the normal action of these hormones.

Bicalutamide is an anti-androgen that can be used to treat prostatecancer. Bicalutamide is a member of the nonsteroidal antiandrogen groupof medications and works by blocking the androgen receptor. Bicalutamidehas been associated with a number of side effects, which may be due, inpart, to the relatively high amounts of bicalutamide that areadministered systemically to obtain a therapeutic benefit. Thus, localadministration of smaller amounts of bicalutamide may be able to achievea therapeutic benefit, and prevent or reduce side effects or toxicity ofsystemic bicalutamide administration.

SUMMARY OF THE DISCLOSURE

A need exists for improved drug implants that can be used to deliver atherapeutically active agent (e.g., bicalutamide) directly to a targettissue of a subject. Provided herein are drug implants that can delivera therapeutically effective amount of a drug directly to a targettissue. Further provided herein are drug implants that, when implantedinto a target tissue, result in a high concentration of drug within thetarget tissue, and a low concentration of drug in the systemiccirculation (e.g., in the blood plasma). In some cases, the ability ofthe drug implants provided herein to deliver a therapeutically effectiveamount of the drug directly to the target tissue, while achieving lowconcentrations of the drug in the systemic circulation, may reduce oreliminate toxicity of the drug that would otherwise occur from systemicadministration. In addition, delivery of the drug directly to the targettissue by way of the drug implants described herein, ensures that thetarget tissue receives a therapeutically effective amount of drug. Infurther aspects, the drug implants provided herein are capable of beingloaded with a large amount of drug such that the drug implant is capableof sustained release of the drug to the target tissue for extendedperiods of time.

In one aspect, an implant is provided comprising bicalutamide dispersedin a polymer matrix, resulting in sustained release of the bicalutamideat a rate of at least 0.1 μg/day for least 6 months after implantationof the implant in a prostate tissue or a tissue near a prostate. In somecases, the bicalutamide is in solid form. In some cases, a volume of theimplant is at least 10 mm³. In some cases, a length of the implant is atleast 1 mm. In some cases, a length of the implant is at least 3 mm. Insome cases, a diameter of the implant is at least 0.1 mm. In some cases,a diameter of the implant is at least 0.8 mm. In some cases, the implantlacks at least one of a sheath, a scaffold, a retention member forretaining the implant within a target tissue, or a combination thereof.In some cases, the implant comprises the bicalutamide in an amount of atleast 30% w/w. In some cases, a total dose of the bicalutamide perimplant is at least 1 mg. In some cases, the polymer matrix comprisessilicone. In some cases, the silicone has a Shore A hardness of at least30 durometer. In some cases, the bicalutamide has a median particle sizeof less than 10 microns. In some cases, the bicalutamide has a D90 ofless than 15 microns. In some cases, the cumulative release of thebicalutamide in an in vitro model is at least one of the following: atleast 100 μg on day 1, at least 1,500 μg on day 50, or at least 2,000 μgon day 100. In some cases, the implant is configured for delivery to theprostate tissue or the tissue near the prostate through a lumen of aneedle or a catheter. In some cases, the implant consists essentially ofthe polymer matrix and the bicalutamide dispersed in the polymer matrix.

In another aspect, a method of treating a subject in need thereof isprovided, the method comprising delivering an implant of any one of thepreceding to the prostate tissue or the tissue near the prostate of thesubject, thereby treating the subject. In some cases, the subject has aproliferative disease of the prostate. In some cases, the proliferativedisease of the prostate is prostate cancer or benign prostatichyperplasia.

In another aspect, a prostate implant is provided comprising: a polymermatrix; and bicalutamide dispersed in the polymer matrix at an amount ofat least 30% w/w. In some cases, the prostate implant releases at least0.1 μg/day of the bicalutamide at 6 months after implantation in asubject. In some cases, the bicalutamide is in solid form. In somecases, the solid form has a median particle size of less than 10microns. In some cases, the solid form has a D90 of less than 15microns. In some cases, the prostate implant has a Shore A hardness ofat least 30 durometer. In some cases, the polymer matrix is a silicone.In some cases, the silicone has one or more of the following propertiesa Shore A hardness of at least 30 durometer and a curing temperatureless than a melting point of bicalutamide. In some cases, at least 50%of the bicalutamide remains in the polymer matrix after 100 days ofimplantation. In some cases, the polymer matrix inhibits modulation ofthe bicalutamide in the prostate implant. In some cases, the modulationcomprises degradation. In some cases, the degradation is determined bymeasuring an amount of the bicalutamide in an eluent after incubatingthe prostate implant containing the bicalutamide in a solutioncomprising 1% SDS containing 0.05 N NaOH for 8 hours at 37° C. In somecases, a volume of the prostate implant is at least 10 mm³. In somecases, a length of the prostate implant is from 1 mm to 30 mm. In somecases, a length of the prostate implant is from 5 mm to 25 mm. In somecases, a diameter of the prostate implant is from 0.1 mm to 1.5 mm. Insome cases, the bicalutamide is dispersed in the polymer matrix at anamount of at least 40% w/w. In some cases, at least 50% of an outersurface of the prostate implant is configured to directly contact aprostate tissue or a tissue near a prostate. In some cases, the prostateimplant is deliverable using a cannula of a prostate biopsy needle or aMick® needle. In some cases, the prostate implant consists essentiallyof the polymer matrix and the bicalutamide dispersed in the polymermatrix.

In another aspect, a method of treating a proliferative disease of theprostate of a subject is provided, the method comprising implanting oneor more implants into a prostate tissue or a tissue near a prostate,wherein each of the one or more implants comprises a polymer matrix andbicalutamide, and wherein the one or more implants provides atherapeutically effective amount of the bicalutamide to the prostate forat least 6 months. In some cases, the proliferative disease of theprostate is prostate cancer or benign prostatic hyperplasia. In somecases, the bicalutamide is dispersed within the polymer matrix, prior tothe implanting. In some cases, the implanting comprises deploying eachimplant of the one or more implants to the prostate tissue or the tissuenear the prostate through a lumen of a needle or a catheter. In somecases, the needle is a Mick® needle. In some cases, the implantingoccurs via transperineal administration. In some cases, thetransperineal administration comprises using a template guided needle.In some cases, the polymer matrix inhibits degradation of thebicalutamide. In some cases, the degradation is determined by measuringan amount of the bicalutamide in an eluent after incubating an implantof the one or more implants in a solution comprising 1% SDS containing0.05 NaOH for 8 hours at 37° C. In some cases, the polymer matrix issubstantially non-biodegradable. In some cases, the polymer matrixcomprises silicone. In some cases, a total dose of the bicalutamideadministered to the subject is less than a total dose of bicalutamidewhen administered to a subject by oral administration. In some cases,the total dose of the bicalutamide administered to the subject is lessthan 100 mg over a period of 6 months. In some cases, the implantingresults in a blood plasma concentration of bicalutamide that is lessthan a blood plasma concentration of bicalutamide obtained whenbicalutamide is administered to a subject by oral administration, andwherein the implanting results in a steady state blood plasmaconcentration of (R)-bicalutamide that is less than 5 μg/mL. In somecases, the implanting comprises transperineal implantation of at leastthree implants. In some cases, each of the one or more implants has avolume of at least 10 mm³.

In another aspect, a method of treating a proliferative disease of theprostate of a subject is provided, the method comprising implanting oneor more implants into a prostate tissue or a tissue near a prostate,wherein each of the one or more implants comprises a polymer matrix andbicalutamide, and wherein the implanting results in a steady state bloodplasma concentration of (R)-bicalutamide that is less than 5 μg/mL. Insome cases, the implanting comprises deploying each implant of the oneor more implants to the prostate tissue or the tissue near the prostatethrough a lumen of a needle or a catheter. In some cases, a total doseof the bicalutamide administered to the subject is less than a totaldose of bicalutamide when administered to a subject by oraladministration. In some cases, the total dose of the bicalutamideadministered to the subject is less than 100 mg over a period of 6months.

In one aspect, an implant is provided comprising a biocompatible,substantially non-biodegradable polymer matrix; and an anti-androgendispersed throughout the polymer matrix. In another aspect, an implantis provided comprising a biocompatible polymer matrix; and atherapeutically active agent dispersed throughout the polymer matrix,wherein the implant delivers a therapeutically effective amount of thetherapeutically active agent to a target tissue of a subject for atleast 24 months when the implant is disposed in the target tissue of thesubject. In another aspect, an implant is provided comprising abiocompatible, substantially non-biodegradable polymer matrix; and ananti-androgen in crystalline form. In yet another aspect, an implant isprovided comprising a biocompatible, substantially non-biodegradablepolymer matrix; and an anti-androgen dispersed throughout the polymermatrix at an amount from 10 to 70% w/w.

In some cases, the implant, when disposed in the target tissue of thesubject, releases at least 0.1 μg/day of the therapeutically activeagent or the anti-androgen at 24 months after implantation. In somecases, the therapeutically active agent or the anti-androgen has amedian particle size of less than 10 microns. In some cases, the implanthas a Shore A hardness of at least 30 durometer when loaded with 60% w/wof a therapeutically active agent. In some cases, at least 99% of thepolymer matrix remains in the target tissue of the subject afterimplantation for at least 600 days. In some cases, the implant isvisible by ultrasound when disposed in the target tissue of the subject.In some cases, the therapeutically active agent or the anti-androgen hasa melting temperature that is greater than a curing temperature of thepolymer matrix. In some cases, the melting temperature is greater than150° C. In some cases, the polymer matrix inhibits degradation of thetherapeutically active agent or the anti-androgen in the implant. Insome cases, the polymer matrix inhibits degradation of thetherapeutically active agent or the anti-androgen by an esterase or anamidase. In some cases, the degradation is determined by measuring theamount of the therapeutically active agent or the anti-androgen in aneluent after incubating the implant containing the therapeuticallyactive agent or the anti-androgen in a solution comprising 1% SDScontaining 0.05 N NaOH for 8 hours at 37° C. In some cases, the implantis elongate. In some cases, the implant is cylindrical. In some cases,the implant is tubular. In some cases, a diameter of the implant is lessthan 1 mm. In some cases, a diameter of the implant is from 0.5 mm to1.5 mm. In some cases, a diameter of the implant is from 0.7 mm to 1.3mm. In some cases, a diameter of the implant is from 0.9 mm to 1.1 mm.In some cases, a diameter of the implant is about 1 mm. In some cases, alength of the implant is less than 20 mm. In some cases, a length of theimplant is from 5 mm to 25 mm. In some cases, a length of the implant isfrom 10 mm to 20 mm. In some cases, a length of the implant is from 12mm to 18 mm. In some cases, a length of the implant is about 15 mm. Insome cases, the implant further comprises a coating. In some cases, thecoating partially covers the implant. In some cases, the coatingsubstantially covers the implant. In some cases, the coating covers theimplant. In some cases, the therapeutically active agent is ananti-androgen. In some cases, the therapeutically active agent or theanti-androgen is bicalutamide. In some cases, the implant is sterile. Insome cases, the implant is disposed in a sterilized package. In somecases, the polymer matrix is at least 95% cured, at least 96% cured, atleast 97% cured, at least 98% cured, at least 99% cured, or at least99.9% cured. In some cases, the polymer matrix comprises silicone. Insome cases, the silicone is Silbione® LSR D370 as manufactured by Elkem.In some cases, the silicone is DDU 4870 as manufactured by NuSil™. Insome cases, the implant is configured to be implanted into prostatetissue of a subject. In some cases, the implant lacks a metal.

In another aspect, a method of manufacturing an implant suitable forimplantation into the prostate of a subject is provided, the methodcomprising: (a) mixing an amount of uncured biocompatible, substantiallynon-biodegradable polymer with an amount of anti-androgen to form amixture; (b) molding the mixture to create a molded mixture; and (c)curing the molded mixture by heating the molded mixture for a period oftime. In some cases, the amount of anti-androgen is between 10% w/w and70% w/w of the uncured biocompatible, substantially non-biodegradablepolymer. In some cases, the anti-androgen is bicalutamide. In somecases, the biocompatible, substantially non-biodegradable polymer is asilicone. In some cases, the silicone is Silbione® LSR D370 asmanufactured by Elkem. In some cases, the silicone is DDU 4870 asmanufactured by NuSil™. In some cases, the curing of (c) furthercomprises heating the molded mixture at a temperature from about 150° C.to about 200° C. for 3 to 8 minutes. In some cases, the mixture furthercomprises a solvent. In some cases, the solvent is selected from thegroup consisting of: pentane, dichloromethane, tetrahydrofuran, heptane,toluene, and hexane. In some cases, the mixture is molded by a transfermolding process. In some cases, the method further comprises performingan analysis on the implant. In some cases, the analysis is selected fromthe group consisting of: differential scanning calorimetry (DSC),deployment of implant in surrogate tissue, elution testing, viscometry,high pressure liquid chromatography (HPLC), and simulated in vivostability assay.

In another aspect, a kit is provided comprising: a sterilized packagecomprising an implant according to any one of the preceding; andinstructions for implanting the implant into a target tissue of asubject. In some cases, the implant is configured for delivery into ahuman prostate, tissue adjacent the human prostate, or both. In somecases, the sterilized package is formed from a foil. In some cases, thekit further comprises one or more surgical tools for implanting theimplant into the target tissue of the subject. In some cases, the one ormore surgical tools comprises a needle, forceps, a trocar, or a stylet.

In another aspect, a method of treating a disease in a subject in needthereof is provided, comprising: implanting an implant of any one of thepreceding into the prostate of the subject, thereby treating thedisease. In another aspect, a method of treating a disease in a subjectin need thereof is provided, comprising: implanting a substantiallynon-biodegradable implant comprising a biocompatible polymer matrix andan anti-androgen drug dispersed throughout the biocompatible polymermatrix into the prostate of the subject, thereby treating the disease.

In some cases, the prostate comprises prostate tissue, tissue adjacentthe prostate tissue, or both. In some cases, the disease is aproliferative disease or disorder of the prostate (e.g., prostatecancer, benign prostatic hyperplasia). In some cases, the method furthercomprises disposing a distal end of an elongate tube in the subject'sprostate or tissue adjacent the prostate. In some cases, a portion ofthe elongate tube is disposed through a first portion of a grid suchthat a first position of the elongate tube in the subject is determined.In some cases, the elongate tube is a needle or a catheter. In somecases, a trocar is disposed within a lumen of the elongate tube. In somecases, the method further comprises removing the trocar from the lumenof the elongate tube. In some cases, the method further comprises afterremoving the trocar from the lumen of the elongate tube, positioning theimplant within the lumen of the elongate tube. In some cases, the methodfurther comprises pushing a stylet through the lumen of the elongatetube, thereby displacing the implant to the distal end of the elongatetube. In some cases, the method further comprises displacing theelongate tube away from the subject such the implant remains within thesubject. In some cases, the stylet is disposed in a portion of the lumenof the elongate tube, a distal end of the stylet adjacent the implantsuch that the implant remains within the subject. In some cases, aportion of a second elongate tube is disposed through a second portionof the grid such that a position of the second elongate tube in thesubject is determined.

BRIEF DESCRIPTION OF THE DRAWINGS

Various aspect of the disclosure are set forth with particularity in theappended claims. A better understanding of the features and advantagesof the present disclosure will be obtained by reference to the followingdetailed description that sets forth illustrative embodiments, in whichthe principles of the disclosure are utilized, and the accompanyingdrawings of which:

FIG. 1 depicts a non-limiting example of a molded implant according toaspects of the disclosure.

FIG. 2A, FIG. 2B, FIG. 2C, FIG. 2D, FIG. 2E, and FIG. 2F depictnon-limiting examples of differential scanning calorimetry (DSC)thermograms of formulation components and molded rods according toaspects of the disclosure.

FIG. 3A, FIG. 3B, and FIG. 3C depict non-limiting examples of ultrasoundimages of an implant in dog prostate (FIG. 3A and FIG. 3B) and a pictureof an explant 8 weeks post implantation (FIG. 3C) according to aspectsof the disclosure.

FIG. 4A depicts non-limiting examples of in vitro elution curves for 30%w/w, 45% w/w, and 60% w/w bicalutamide implants according to aspects ofthe disclosure.

FIG. 4B depicts non-limiting examples of in vitro elution curves for 30%w/w and 45% w/w bicalutamide with various silicone implants.

FIG. 4C depicts projected elution curves for bicalutamide-loadedimplants up to 24 months.

FIG. 4D depicts a cumulative release profile of an implant containing60% w/w bicalutamide in an in vitro model.

FIG. 4E depicts a release rate profile of an implant containing 60% w/wbicalutamide in an in vitro model.

FIG. 4F depicts a predicted cumulative release profile of an implantcontaining 60% w/w bicalutamide in an in vitro model.

FIG. 4G depicts cumulative release profiles of implants containing 60%w/w bicalutamide in an in vitro model.

FIG. 4H depicts release rate profiles of implants containing 60% w/wbicalutamide in an in vitro model.

FIG. 5 depicts a non-limiting example of results obtained from asimulated in vivo stability assay.

FIG. 6A and FIG. 6B depict non-limiting examples of bicalutamide levelsin plasma after implantation of devices of the disclosure into theprostate of canines.

FIG. 7A and FIG. 7B depict non-limiting examples of bicalutamide levelsin tissue after implantation of devices of the disclosure into theprostate of canines.

FIG. 8 depicts an image and a schematic of implant locations and localdistribution of R-bicalutamide (active levels) in the rostral portion ofthe prostate of canines.

DETAILED DESCRIPTION OF THE DISCLOSURE

Provided herein are drug implants that are capable of delivering atherapeutically effective amount of a drug directly to a target tissue.Further provided herein are drug implants that, when implanted into atarget tissue, result in a high concentration of drug within the targettissue, and a low concentration of drug in the systemic circulation(e.g., in the blood plasma). In some cases, the ability of the drugimplants provided herein to deliver a therapeutically effective amountof the drug directly to the target tissue, while achieving lowconcentrations of the drug in the systemic circulation, may reduce oreliminate side effects or toxicity of the drug that would otherwiseoccur from systemic administration. In addition, delivery of the drugdirectly to the target tissue by way of the drug implants describedherein, ensures that the target tissue receives a therapeuticallyeffective amount of drug. In further aspects, the drug implants providedherein are capable of being loaded with a large amount of drug such thatthe drug implant is capable of sustained release of the drug to thetarget tissue for extended periods of time. In some aspects, thetherapeutically active agent may be dispersed within a polymer matrix ofthe implant which may provide particular advantages (e.g., fasterelution times, higher drug loading within the implant, etc.). Inparticular aspects, the drug implants provided herein may containbicalutamide at high concentrations such that a therapeuticallyeffective amount of bicalutamide can be administered directly toprostate tissue for long periods of time (6 months or greater) whilemaintaining low systemic concentrations of bicalutamide.

In various aspects, the drug implants disclosed herein may comprise apolymer matrix and a therapeutically active agent. In particular cases,the therapeutically active agent may be dispersed within the polymermatrix. The drug implants may be implanted into a target tissue, and mayrelease a quantity of the therapeutically active agent over time. Thetherapeutically active agent may be a drug or active pharmaceuticalingredient (API) that may be effective to treat a disease or a symptomthereof. In some cases, the therapeutically active agent isbicalutamide, and the disease is a proliferative disease of the prostate(e.g., prostate cancer, benign prostatic hyperplasia). Further providedherein are methods of treating a disease by delivering a drug implant ofthe disclosure to a target tissue of a subject in need thereof in orderto deliver a therapeutically effective amount of drug for extendedperiods of time. Additionally, methods of manufacturing drug implantsand kits including drug implants are provided.

Drug Implants

Provided herein are drug implants (also referred to herein as“implants”) suitable for delivering a therapeutically active agent to atarget tissue. In some aspects of the disclosure, the implant comprisesa polymer matrix and a therapeutically active agent dispersed therein.The therapeutically active agent or drug may be bicalutamide. Theimplants may be suitable for treating a proliferative disease of theprostate (e.g., prostate cancer, benign prostatic hyperplasia).

The polymer matrix may comprise any polymer material. Generally, thepolymer material may be biocompatible. The term “biocompatible” as usedherein refers to a property of a material that allows for prolongedcontact with a tissue in a subject without causing toxicity orsignificant damage.

In some aspects, the polymer material may be “non-biodegradable” or“substantially non-biodegradable”. The terms “non-biodegradable” or“substantially non-biodegradable”, when used in reference to an implantof the disclosure, generally refer to an implant that is incapable orsubstantially incapable of being decomposed by microorganisms over theintended life of the implant. For example, a substantiallynon-biodegradable implant of the disclosure may have at least 99% of thepolymer material remaining two years after implanting the device into atarget tissue.

In certain aspects of the disclosure, the polymer matrix may comprisepolysiloxane (silicone). The silicone may be any biocompatible silicone.In some cases, the silicone may be a medical grade silicone. In somecases, the silicone may be a United States Pharmacopeia (USP) Class V orUSP Class VI certified silicone. In various aspects, the silicone may beany liquid silicone rubber (LSR). In some cases, the silicone may be aSilbione® Liquid Silicone Rubber (LSR) as manufactured by Elkem. In somecases, the Silbione® LSR may be one or more of Silbione® LSR 4301,Silbione® LSR 4305, Silbione® LSR 4310, Silbione® LSR 4325, Silbione®LSR 4330, Silbione® LSR 4340, Silbione® LSR 4350, Silbione® LSR 60,Silbione® LSR 4360, Silbione® LSR 4370, Silbione® LSR 4745, Silbione®LSR 4755, Silbione® LSR 4765, Silbione® LSR 4125, Silbione® LSR 4130,Silbione® LSR 4140, Silbione® LSR M301, Silbione® LSR M305, Silbione®LSR M310, Silbione® LSR M325, Silbione® LSR M330, Silbione® LSR M340,Silbione® LSR M350, Silbione® LSR M360, Silbione® LSR M365, Silbione®LSR M370, Silbione® LSR M125, Silbione® LSR M130, Silbione® LSR M140. Invarious aspects, the silicone may be Silbione® LSR D370. In some cases,the silicone may be a silicone manufactured by NuSil™. In variousaspects, the silicone may be DDU 4870 as manufactured by NuSil™. In somecases, the silicone may be one or more of the following silicones asmanufactured by NuSil™: MED-4801, MED-4805, MED-4810, MED-5820,MED-5830, MED-5840, MED-5850, MED-5860, MED-5870, MED-4880, MED50-5338,MED-5440, MED-4842, and MED1-4855.

Additional non-biodegradable polymers which may be used herein include,without limitation, a silicone material, acrylates, polyethylenes,polyurethane, hydrogel, polyester, polypropylene,polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE), polyether etherketone (PEEK), nylon, extruded collagen, polymer foam, silicone rubber,polyethylene terephthalate, ultra-high molecular weight polyethylene,polycarbonate urethane, polyurethane, and polyimides.

The Shore A hardness scale measures the hardness of rubbers. A highernumber on the scale refers to a firmer material, whereas a lower numberon the scale refers to a softer material. Generally, the polymermaterial in the drug implant has a Shore A hardness of at least30-durometer. For example, the polymer material may have a Shore Ahardness of at least 30-durometer, at least 40-durometer, at least50-durometer, at least 60-durometer, or at least 70-durometer. In oneaspect, the uncured polymer material may have a Shore A hardness of30-durometer, and the cured polymer material may have a Shore A hardnessof 70-durometer.

The implant may further comprise a therapeutically active agent (alsoreferred to herein as a “drug”). In particular aspects, thetherapeutically active agent is bicalutamide. In some cases, thetherapeutically active agent may be dispersed or distributed within thepolymer matrix. In some cases, the therapeutically active agent may bedispersed or distributed throughout the polymer matrix. In some cases,the therapeutically active agent may be uniformly or homogeneouslydispersed or distributed within the polymer matrix. In other cases, thetherapeutically active agent may be heterogeneously dispersed ordistributed within the polymer matrix. In other cases, thetherapeutically active agent may be dispersed or distributed within thepolymer matrix in a gradient. In particular aspects, the therapeuticallyactive agent may be dispersed or distributed within the polymer matrixat the time of manufacture of the implant (e.g., the therapeuticallyactive agent may be mixed with the polymer material prior to curing ofthe polymer material as disclosed herein). In some cases, providing thedrug dispersed within the polymer matrix may be advantageous over otherdrug implants (e.g., those in which the drug is encapsulated in acapsule, or in the lumen of a tube). For example, having the drugdispersed within the polymer matrix may allow for higher loading of drugin the implant, faster elution rates, and the like.

In various aspects of the disclosure, the implant may comprise atherapeutically active agent (e.g., bicalutamide) in an amount fromabout 10% w/w to about 70% w/w. For example, the implant may comprise atherapeutically active agent (e.g., bicalutamide) in an amount of about10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w,about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55%w/w, about 60% w/w, about 65% w/w, or about 70% w/w. In various aspects,the implant may comprise a therapeutically active agent (e.g.,bicalutamide) in an amount of at least about 10% w/w, at least about 15%w/w, at least about 20% w/w, at least about 25% w/w, at least about 30%w/w, at least about 35% w/w, at least about 40% w/w, at least about 45%w/w, at least about 50% w/w, at least about 55% w/w, at least about 60%w/w, at least about 65% w/w, or at least about 70% w/w. In particularaspects, the therapeutically active agent is bicalutamide and is presentin the implant in an amount of about 10% w/w, about 30% w/w, about 45%w/w, or about 60% w/w. In some cases, the disclosure provides drugimplants loaded with high concentrations of bicalutamide (e.g., 60%w/w). In some cases, the implant may contain bicalutamide in an amountof at least 30% w/w. In some cases, the implant may contain bicalutamidein an amount of at least 40% w/w.

In various aspects of the disclosure, the implant may comprise atherapeutically active agent (e.g., bicalutamide) in an amount fromabout 5% volume/volume (v/v) to about 60% v/v. For example, the implantmay comprise a therapeutically active agent (e.g., bicalutamide) in anamount of about 5% v/v, about 10% v/v, about 15% v/v, about 20% v/v,about 25% v/v, about 30% v/v, about 35% v/v, about 40% v/v, about 45%v/v, about 50% v/v, about 55% v/v, or about 60% v/v. In various aspects,the implant may comprise a therapeutically active agent (e.g.,bicalutamide) in an amount of at least about 5% v/v, at least about 10%v/v, at least about 15% v/v, at least about 20% v/v, at least about 25%v/v, at least about 30% v/v, at least about 35% v/v, at least about 40%v/v, at least about 45% v/v, at least about 50% v/v, at least about 55%v/v, or at least about 60% v/v. In particular aspects, thetherapeutically active agent is bicalutamide and is present in theimplant in an amount of at least 30% v/v.

In various aspects, an implant of the disclosure may includebicalutamide in a total amount of at least 1 mg, for example, from about1 mg to about 10 mg. In some cases, the total amount of bicalutamide inthe implant may be from about 8 mg to about 10 mg. For example, theimplant may include bicalutamide in a total amount of about 1 mg, about1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about5.7 mg, about 5.8 mg, about 5.9 mg, about 6.0 mg, about 6.1 mg, about6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg, about 7.1 mg, about7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about7.7 mg, about 7.8 mg, about 7.9 mg, about 8.0 mg, about 8.1 mg, about8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about9.7 mg, about 9.8 mg, about 9.9 mg, or about 10.0 mg.

In various aspects of the disclosure, the polymer material may be curedwith the bicalutamide present therein. Without wishing to be bound bytheory, curing refers to a chemical process that results in thehardening of a polymer material by cross-linking polymer chains. Anymethod may be used to cure a polymer of the disclosure, including theuse of electron beams, heating, and/or the addition of additives. Invarious aspects of the disclosure, the bicalutamide may be mixed with anuncured polymer material prior to curing. In some aspects, the polymermatrix may be at least 95% cured, at least 96% cured, at least 97%cured, at least 98% cured, at least 99% cured, at least 99.9% cured, or100% cured.

Generally, the polymer material has a curing temperature that is lowerthan the melting temperature of the therapeutically active agent, e.g.,to prevent melting and/or degradation of the drug. For example, thepolymer material may have a curing temperature that is lower than amelting temperature of bicalutamide. In some cases, polymer material mayhave a curing temperature that is lower than 190° C., lower than 185°C., lower than 180° C., lower than 175° C., lower than 170° C., lowerthan 165° C., lower than 160° C., lower than 155° C., or lower than 150°C. In a particular example, bicalutamide may have a melting temperatureof about 180° C.-190° C., and the polymer may have a curing temperatureof less than about 190° C. (e.g., about 170° C.).

In various aspects of the disclosure, the bicalutamide may be present inthe implant in solid form. In some cases, the solid bicalutamide may bedissolved upon contact with biological fluids (e.g., after implantationinto a tissue), and may diffuse out of the implant and into the targettissue. In some cases, the bicalutamide is present in the implant incrystalline form. In general, the particle size of the bicalutamidewithin the implant may be important for drug content uniformity withinthe implant. Without wishing to be bound by theory, a small particlesize may ensure a uniform distribution within the formulation andbetween implants upon molding of the formulation. In some cases, thebicalutamide present in the implant may have a median particle size(e.g., D50 particle size) of less than 10 μm. In some cases, thebicalutamide present in the implant may have a D90 particle size of lessthan 15 μm.

In various aspects of the disclosure, the implant may further compriseadditional molecules that are incapable of eluting from the implant. Insome cases, these additional molecules may result in higher elutionrates of the drug. Non-limiting examples of additional molecules thatmay be present within the implant include sugars (e.g., lactose), salts,fused silica, cellulose, and high molecular weight polyethylene glycol(PEG).

Generally, an implant of the disclosure has mechanical properties suchthat the implant can be successfully deployed into a target tissue. Forexample, an implant of the disclosure may be sufficiently stiff suchthat it can be deployed into a target tissue successfully, but not toostiff that it breaks during deployment. It should be understood that themechanical properties of devices described herein may vary depending onthe polymer material used, and may be determined empirically. In someaspects, the implant containing the bicalutamide may have a Shore Ahardness of at least 30 durometer.

In various aspects, the implant may have a three-dimensional shape. Thethree-dimensional shape may be any suitable shape. In some cases, theimplant may be cylindrical or substantially cylindrical. In some cases,the implant may be tubular or substantially tubular. In some cases, theimplant may be elongate (e.g., may have a length greater than a width).In some cases, the implant may be not hollow. In some cases, the implantmay be a rod or rod-like.

In various aspects, the implant may have a diameter. In some cases, adiameter of the implant may be from about 0.1 mm to about 1.5 mm. Insome cases, a diameter of the implant may be from about 0.7 mm to about1.3 mm. In some cases, a diameter of the implant may be from about 0.9mm to about 1.1 mm. In some cases, a diameter of the implant may be atleast about 0.1 mm, for example, at least about 0.1 mm, at least about0.2 mm, at least about 0.3 mm, at least about 0.4 mm, at least about 0.5mm, at least about 0.6 mm, at least about 0.7 mm, at least about 0.8 mm,at least about 0.9 mm, at least about 1.0 mm, at least about 1.1 mm, atleast about 1.2 mm, at least about 1.3 mm, at least about 1.4 mm, or atleast about 1.5 mm. In some cases, a diameter of the implant may be lessthan about 1 mm, for example, less than about 1 mm, less than about 0.9mm, less than about 0.8 mm, less than about 0.7 mm, less than about 0.6mm, less than about 0.5 mm, less than about 0.4 mm, less than about 0.3mm, less than about 0.2 mm, or less than about 0.1 mm. In some cases, adiameter of the implant may be at least about 0.1 mm. In some case, adiameter of the implant may be at least about 0.8 mm. In some cases, adiameter of the implant may be about 1 mm.

In various aspects, the implant may have a length. In some cases, alength of the implant may be from about 1 mm to about 30 mm. In somecases, a length of the implant may be from about 5 mm to about 25 mm. Insome cases, a length of the implant may be from about 10 mm to about 20mm. In some cases, a length of the implant may be from about 12 mm toabout 18 mm. In some cases, a length of the implant may be at leastabout 1 mm, at least about 2 mm, at least about 3 mm, at least about 4mm, at least about 5 mm, at least about 6 mm, at least about 7 mm, atleast about 8 mm, at least about 9 mm, at least about 10 mm, at leastabout 11 mm, at least about 12 mm, at least about 13 mm, at least about14 mm, at least about 15 mm, at least about 16 mm, at least about 17 mm,at least about 18 mm, at least about 19 mm, at least about 20 mm, atleast about 21 mm, at least about 22 mm, at least about 23 mm, at leastabout 24 mm, at least about 25 mm, at least about 26 mm, at least about27 mm, at least about 28 mm, at least about 29 mm, or at least about 30mm. In some cases, a length of the implant is at least about 1 mm. Insome cases, a length of the implant is at least about 3 mm. In somecases, a length of the implant is about 15 mm. In some cases, a lengthof the implant may be less than about 30 mm, for example, less thanabout 30 mm, less than about 29 mm, less than about 28 mm, less thanabout 27 mm, less than about 26 mm, less than about 25 mm, less thanabout 24 mm, less than about 23 mm, less than about 22 mm, less thanabout 21 mm, less than about 20 mm, less than about 19 mm, less thanabout 18 mm, less than about 17 mm, less than about 16 mm, less thanabout 15 mm, less than about 14 mm, less than about 13 mm, less thanabout 12 mm, less than about 11 mm, less than about 10 mm, less thanabout 9 mm, less than about 8 mm, less than about 7 mm, less than about6 mm, less than about 5 mm, less than about 4 mm, less than about 3 mm,less than about 2 mm, or less than about 1 mm.

In various aspects, the implant may have a volume. In some cases, thevolume of the implant may be from about 0.1 mm³ to about 30 mm³. Forexample, the volume of the implant may be about 0.1 mm³, about 0.5 mm³,about 1 mm³, about 5 mm³, about 10 mm³, about 15 mm³, about 20 mm³,about 25 mm³, or about 30 mm³. In some cases, the volume of the implantmay be about 10 mm³.

In various aspects, the implant may lack a coating, covering, or asheath. For example, in some cases, a portion of the outer surface ofthe implant may not be coated or covered such that the outer surface ofthe uncoated or uncovered portion of the implant is directly exposed toor directly contacts the biological environment (e.g., a target tissue,a biological fluid) after implantation. In some examples, the entireouter surface or substantially the entire outer surface of the implantis uncovered or uncoated such that the entire outer surface orsubstantially the entire outer surface of the implant is directlyexposed to or directly contacts a biological environment afterimplantation. In other cases, less than the entire outer surface of theimplant is directly exposed to or directly contacts a biologicalenvironment after implantation. For example, in some cases, at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, at least 45%, at least 50%, at least 55%, at least60%, at least 65%, at least 70%, at least 75%, at least 80%, at least85%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least99% of the outer surface of the implant is directly exposed to ordirectly contacts a biological environment after implantation. In somecases, at least 50% of the outer surface of the implant is directlyexposed to or directly contacts a biological environment afterimplantation. In some cases, the implant may lack a sheath, a scaffold,a retention member, a retention frame, or any other additional means forretaining the implant within the target tissue. In some cases, theimplant may consist essentially of the polymer matrix and thetherapeutically active agent (e.g., bicalutamide) dispersed therein.

In some cases, the implant may comprise a coating. In some cases, thecoating may cover the implant. In some cases, the coating may partiallycover the implant. In some cases, the coating may substantially coverthe implant. In some cases, the implant may comprise a core made of afirst polymer material, and a coating of a second polymer material. In anon-limiting example, an implant of the disclosure may include anon-silicone core, surrounded by a silicone coating. In some cases, animplant of the disclosure does not comprise a metal.

In various aspects, the implant may prevent modulation of thebicalutamide contained therein when the implant is implanted into asubject. Modulation can include, but is not limited to, degradation,chemical modification, and the like. For example, the biologicalenvironment of a tissue may include degradants that are capable ofdegrading the drug (e.g., esterases, amidases). In some cases, theimplant may protect the therapeutically active agent from degradation bypreventing the degradant from penetrating the implant. In variousaspects, in vitro stability testing may be performed to determine theprotective effect of the implant on the therapeutically active agentcontained therein. For example, when the therapeutically active agent isbicalutamide, degradation may be determined by measuring the amount ofthe bicalutamide in an eluent after incubating the implant containingthe bicalutamide in a solution comprising 1% SDS containing 0.05 N NaOHfor 8 hours at 37° C. (e.g., in vivo stability testing, a non-limitingexample of which has been provided in Example 2). In such cases, thetherapeutically active agent may be capable of diffusing out of theimplant while maintaining in vivo stability within the implant. Invarious aspects, the ability of a degradant to degrade a therapeuticallyactive agent within the implant may be determined by a simulated in vivostability assay, for example, as described in Example 2. In anon-limiting example, an implant of the disclosure comprising atherapeutically active agent may be incubated in a solution comprising adegradant (known to degrade the therapeutically active agent). After aperiod of incubation, the therapeutically active agent may be extractedfrom the implant and degradation peaks may be measured (e.g., byhigh-performance liquid chromatography (HPLC)).

In various aspects of the disclosure, an implant of the disclosure maybe configured to be delivered directly to a target tissue of a subject.In some cases, the target tissue may be prostate tissue. In some cases,an implant of the disclosure may be configured to be delivered to atissue adjacent to or nearby a target tissue. In some cases, thetherapeutically active agent may diffuse out of the implant in acontrolled manner and act directly on the target tissue.

In various aspects, an implant of the disclosure may be configured toremain within the target tissue for a period of time. In some cases, animplant of the disclosure may be configured to remain within the targettissue indefinitely (e.g., is never removed). In some cases, two or moreimplants of the disclosure may be implanted into the target tissue. Forexample, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20 or more than 20 implants may be implanted in the target tissue. Insome cases, the two or more implants may be implanted in different sitesof the target tissue (e.g., to deliver drug to different sites of thetarget tissue). In some cases, the two or more implants may be implantedin close proximity to one another within the target tissue. In somecases, one or more initial implants may be implanted, and additionalimplants may be later implanted after the drug has been exhausted fromthe initial implants. For example, one or more additional implants maybe implanted after a drug has stopped, or substantially stopped, elutingfrom one or more initial implants. In some cases, an implant of thedisclosure may be visible by ultrasound when disposed within the targettissue of the subject. In such cases, the position of the implant may bemonitored non-invasively. In some cases, the implant may be sterilizedprior to implantation into a subject. In some cases, the implant issterilized via gamma sterilization.

In various aspects, an implant of the disclosure may be capable ofdelivering a sustained release of the therapeutically active agent for aperiod of time. For example, an implant of the disclosure may be capableof sustained release of the therapeutically active agent. “Sustainedrelease” as used herein refers to the capability of the implant torelease an amount of drug for an extended period of time afterimplantation into a target tissue. In some cases, an implant of thedisclosure may be capable of delivering an amount of drug to a targettissue for at least 6 months, at least 9 months, at least 12 months, atleast 18 months, or at least 24 months. In particular cases, an implantof the disclosure may be capable of delivering at least 0.1 μg/day ofbicalutamide for at least 6 months after implantation into prostatetissue or tissue adjacent or near the prostate. In some cases, animplant of the disclosure may be capable of delivering at least 0.1μg/day of bicalutamide (e.g., to a prostate) for up to 24 months afterimplantation into prostate tissue or tissue adjacent or near theprostate.

Methods for Manufacturing Drug Implants

Further provided herein are methods for manufacturing the implantsdescribed herein. A non-limiting example of a method for manufacturing adrug implant of the disclosure may be as provided in Example 1.

In some aspects, the methods may involve mixing an amount of uncuredpolymer material with an amount of a therapeutically active agent toform a mixture. The methods may further involve molding the mixture tocreate a molded structure. The methods may further involve curing themolded mixture by heating the molded mixture for a period of time. Insome cases, the uncured polymer material may be any biocompatiblesilicone provided herein. In an exemplary aspect, the silicone may beSilbione® LSR D370 or DDU 4870 (as manufactured by NuSil™). In somecases, the therapeutically active agent may be an anti-androgen,examples of which have been provided herein. In an exemplary aspect, thetherapeutically active agent may be bicalutamide.

The therapeutically active agent (e.g., bicalutamide) may be provided inthe curing mixture in an amount such that a total amount of active agentin the implant may be from about 10% w/w to about 70% w/w, for example,about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30%w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about55% w/w, about 60% w/w, about 65% w/w, or about 70% w/w. In some cases,the total amount of active agent in the implant may be at least about10% w/w, at least about 15% w/w, at least about 20% w/w, at least about25% w/w, at least about 30% w/w, at least about 35% w/w, at least about40% w/w, at least about 45% w/w, at least about 50% w/w, at least about55% w/w, at least about 60% w/w, at least about 65% w/w, or at leastabout 70% w/w. In some cases, the therapeutically active agent isbicalutamide. The bicalutamide may be present within the curing mixturesuch that a total amount of bicalutamide in the implant is in an amountof at least 10% w/w, at least 30% w/w, at least 40% w/w, at least 45%w/w, or at least 60% w/w. The bicalutamide may be provided in the curingmixture in an amount such that a total amount of bicalutamide in theimplant may be from about 1 mg to about 10 mg.

In some aspects, the curing comprises heating the molded mixture at 150°C. to 200° C., for example, 150° C., 155° C., 160° C., 165° C., 170° C.,175° C., 180° C., 185° C., 190° C., 195° C., or 200° C. The curingtemperature generally depends on the polymer material selected.Generally, the curing temperature of the polymer material is selectedsuch that it is lower than the melting temperature of thetherapeutically active agent. In some cases, the curing comprisesheating the molded mixture from 3 minutes to 8 minutes, for example, for3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, or 8 minutes. Insome cases, the silicone and active agent may be selected based on thecuring temperature of the silicone and the melting temperature of theactive agent, such that the melting temperature of the active agent maybe greater than the curing temperature of the silicone.

In some aspects, the mixture may further comprise a solvent.Non-limiting examples of solvents that may be used include pentane,heptane, toluene, dichloromethane, tetrahydrofuran, and hexane. In someaspects, the mixture may be molded by a transfer molding process.

After manufacturing the implant as provided herein, the methods mayfurther comprise performing one or more analyses on the implant. In somecases, the one or more analyses may be differential scanning calorimetry(DSC), a non-limiting example of which has been provided in Example 2.In some cases, the one or more analyses may be deployment of the implantinto surrogate tissue, a non-limiting example of which has been providedin Example 2. In some cases, the one or more analyses may be elutiontesting, a non-limiting example of which has been provided in Example 2.In some cases, the one or more analyses may be in vivo stabilitytesting, a non-limiting example of which has been provided in Example 2.In some cases, the one or more analyses may be viscometry. In somecases, the one or more analyses may be high pressure liquidchromatography.

Methods of Treatment

Disclosed herein are methods of treating a disease (or a symptomthereof) in a subject. The terms “treating”, “treatment”, or “treat” maybe used interchangeably herein and refer to providing a therapeuticbenefit to a subject in need thereof. For example, treating a disease ordisorder includes ameliorating, abrogating, reducing, relieving, orcuring the disease or disorder. Treating a disease or disorder alsoincludes ameliorating, abrogating, reducing, relieving, or curing one ormore symptoms associated with a disease or disorder. When used inreference to a tumor, treating includes diminishing or reducing the sizeof the tumor or tumor volume.

In various aspects, the subject may have been diagnosed with, may besuspected of having, or may be at risk of having the disease. In somecases, the methods comprise implanting an implant of the disclosure intoa target tissue of a subject. An implant of the disclosure may beimplanted into a target tissue by any method. In some cases, the implantmay be implanted into a target tissue by a surgical method or anon-surgical method. In some cases, the implant may be implanted usingstandard surgical tools, for example, tools commonly used for biopsiesor brachytherapy. In some cases, the implant may be implanted into atarget tissue by use of, e.g., a needle, forceps, a catheter (e.g., witha lumen). For example, in one embodiment, the implant may be implantedinto a target tissue by deployment from the lumen of a needle or acatheter. In some cases, the implant may be implanted into a targettissue using a cannula of a prostate biopsy needle. In some cases, theimplant may be implanted into a target tissue using a Mick® needle. Insome cases, deployment of the implant may be guided by ultrasound. Insome cases, the implant may be implanted by transperineal implantation(e.g., by use of a template guided needle). In some cases, the implantmay be sterile and disposed within a packaging.

In a non-limiting example, a method of deploying an implant of thedisclosure into a target tissue may involve disposing a distal end of anelongate tube into the target tissue (e.g., the prostate or tissueadjacent the prostate). In some cases, the elongate tube may be a needlehaving a lumen. The elongate tube may have a sharp end such that thedistal end of the elongate tube can penetrate the target tissue. In somecases, the distal end of the elongate tube may be disposed through afirst portion of a grid (e.g., a guide template) such that a firstposition of the elongate tube in the subject is determined. The grid mayallow for proper placement of the implant into the target tissue. Insome cases, a trocar is disposed within the lumen of the elongate tube.The methods may involve inserting the elongate tube (with or without atrocar disposed within a lumen of the elongate tube) into the targettissue. The methods may further involve, when using a trocar, removingthe trocar from the lumen of the elongate tube, while maintaining thedistal end of the elongate tube within the target tissue. The methodsmay further involve placing an implant of the disclosure within thelumen of the elongate tube. The implant may be pushed through the lumenof the elongate tube by a blunt-ended rod (e.g., a stylet) that is sizedto fit within the lumen of the elongate tube. The stylet may be used topush the implant from a proximal end of the elongate tube to the distalend of the elongate tube. The methods may further involve, whilemaintaining the stylet in position, removing the elongate tube from thetarget tissue. As the elongate tube is removed from the target tissue,the stylet may push the implant out of the elongate tube and into thetarget tissue. The methods may further involve removing both the styletand the elongate tube together from the target tissue.

In some aspects, the methods may involve implanting more than oneimplant into a target tissue of the subject. For example, the methodsmay involve implanting a first implant into a first portion of thetarget tissue, and a second implant into a second portion of the targettissue. In some cases, the first portion of the target tissue and thesecond portion of the target tissue may be different. In some cases, thefirst implant may comprise a first therapeutically active agent and thesecond implant may comprise a second therapeutically active agent. Insome cases, the first therapeutically active agent and the secondtherapeutically active agent may be the same. In other cases, the firsttherapeutically active agent and the second therapeutically active agentmay be different. In some cases, a grid (e.g., a guide template) may beused to position the first implant within the first portion of thetarget tissue, and to position the second implant within the secondportion of the target tissue. In some cases, the first implant and/orthe second implant may be positioned with the use of ultrasoundguidance.

In some aspects, the methods may further comprise implanting additionalimplants into the target tissue. For example, the methods may furthercomprise implanting a third implant into a third portion of the targettissue, implanting a fourth implant into a fourth portion of the targettissue, implanting a fifth implant into a fifth portion of the targettissue, implanting a sixth implant into a sixth portion of the targettissue, implanting a seventh implant into a seventh portion of thetarget tissue, implanting an eighth implant into an eighth portion ofthe target tissue, and so forth. The third, fourth, fifth, sixth,seventh, eighth, or more, therapeutically active agents may each be thesame, different, or combinations thereof. In some cases, at least threeimplants are implanted into a target tissue. For example, at least threeimplants may be implanted into the prostate or tissue adjacent or nearthe prostate by transperineal administration.

In some aspects, one or more implants may be implanted into a prostateor tissue adjacent or near a prostate prior to a surgical procedure totreat prostate cancer. For example, one or more implants may beimplanted into a prostate or tissue adjacent or near a prostate prior toperforming a prostatectomy (e.g., a week before, two weeks before, threeweeks before, etc.). In such cases, the prostatectomy may remove theprostate or a portion thereof. In some cases, the prostatectomy mayremove one or more of the implants from the subject. In other cases, oneor more implants may be implanted into a prostate or tissue adjacent ornear a prostate, and may remain in the prostate indefinitely. Forexample, the one or more implants may provide a therapeuticallyeffective amount of bicalutamide to the prostate tissue for a period oftime such that the subject is in remission or cured of the prostatecancer.

The term “subject”, as used herein, generally refers to a vertebrate,such as a mammal, e.g., a human. Mammals include, but are not limitedto, murines, simians, humans, research animals, farm animals, sportanimals, and pets. In some cases, the methods described herein may beused on tissues derived from a subject and the progeny of such tissues.The tissues may be obtained from a subject in vivo. In some cases, thetissues may be cultured in vitro.

In some aspects, the methods provided herein may be used to treat asubject in need thereof. In some cases, the subject may suffer from adisease. In some cases, the subject may be a human. In some cases, thehuman may be a patient at a hospital or a clinic. In some cases, thesubject may be a non-human animal, for example, a non-human primate, alivestock animal, a domestic pet, or a laboratory animal. For example, anon-human animal can be an ape (e.g., a chimpanzee, a baboon, a gorilla,or an orangutan), an old world monkey (e.g., a rhesus monkey), a newworld monkey, a dog, a cat, a bison, a camel, a cow, a deer, a pig, adonkey, a horse, a mule, a lama, a sheep, a goat, a buffalo, a reindeer,a yak, a mouse, a rat, a rabbit, or any other non-human animal.

In cases where the subject may be a human, the subject may be of anyage. In some cases, the subject may be about 50 years or older. In somecases, the subject may be about 55 years or older. In some cases, thesubject may be about 60 years or older. In some cases, the subject maybe about 65 years or older. In some cases, the subject may be about 70years or older. In some cases, the subject may be about 75 years orolder. In some cases, the subject may be about 80 years or older. Insome cases, the subject may be about 85 years or older. In some cases,the subject may be about 90 years or older. In some cases, the subjectmay be about 95 years or older. In some cases, the subject may be about100 years or older. In some cases, the subject may be about 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or greater than 100years old. In some cases, the subject may be about 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or greater than 20years old.

In some cases, the methods provided herein may treat a disease in asubject. In some cases, the methods provided herein may alleviate orreduce a symptom of a disease. In some cases, the methods providedherein may result in a reduction in the severity of one or more symptomsassociated with a disease. In some cases, the methods provided hereinmay slow, halt, or reverse the progression of one or more symptomsassociated with a disease. In some cases, the methods provided hereinmay prevent the development of one or more symptoms associated with adisease. In some cases, the methods provided herein may slow, halt, orreverse the progression of a disease, as measured by the number andseverity of symptoms experienced.

In some cases, the disease may be a proliferative disease or disorder.In some cases, the proliferative disease or disorder may be cancer. Insome cases, the subject may have a tumor. In some cases, the methods mayreduce the size of a tumor. In some cases, the methods may reduce thesize of a tumor by at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, at least 90%, at least 95%, or by 100%.

In some aspects, the proliferative disease or disorder may be aproliferative disease or disorder of the prostate. In one non-limitingexample, the proliferative disease or disorder of the prostate may beprostate cancer. Prostate cancer can be adenocarcinoma, sarcoma,neuroendocrine tumors, small cell carcinoma, transitional cellcarcinoma, or squamous cell carcinoma. In another non-limiting example,the proliferative disease or disorder of the prostate may be benignprostatic hyperplasia.

The methods may be employed to deliver a therapeutically effectiveamount of a drug to a target tissue. In some cases, the methods mayinvolve delivering a drug implant to a target tissue (or a tissueadjacent to the target tissue) of the subject. Any tissue may besuitable for delivery of a drug implant of the disclosure. In exemplarycases, the target tissue may be the prostate, tissue adjacent to theprostate, or both. Non-limiting examples of target tissue includesbreast, pancreas, bladder, brain, skin, kidney, lung, liver, tongue,esophagus, stomach, intestine, gallbladder, heart, pituitary gland,pineal gland, thyroid gland, parathyroid gland, adrenal gland, eye,bone, fallopian tubes, uterus, ovary, sinuses, inner ear (eustachiantube), testes, and neck.

In various aspects of the disclosure, the methods provide for implantinga drug implant of the disclosure into the target tissue (or an adjacenttissue) of a subject, wherein the implant delivers a therapeuticallyeffective amount of the drug to the target tissue. As used herein, a“therapeutically effective amount” when used in reference to a drug ortherapeutically active agent refers to an amount of drug ortherapeutically active agent that is capable of eliciting a therapeuticresponse in a subject. In various aspects of the disclosure, the implantmay deliver a therapeutically effective amount of drug to a tissue ofthe subject from 6 months to 24 months. In some cases, the implant maydeliver a therapeutically effective amount of drug to a tissue of thesubject for 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, 13 months, 14 months, 15 months, 16 months, 17months, 18 months, 19 months, 20 months, 21 months, 22 months, 23months, or 24 months. In some cases, the implant may deliver atherapeutically effective amount of drug to a tissue of the subject forat least 6 months, at least 7 months, at least 8 months, at least 9months, at least 10 months, at least 11 months, at least 12 months, atleast 13 months, at least 14 months, at least 15 months, at least 16months, at least 17 months, at least 18 months, at least 19 months, atleast 20 months, at least 21 months, at least 22 months, at least 23months, or at least 24 months.

In various aspects of the disclosure, a therapeutically effective amountof drug may be at least 0.1 μg/day. In some cases, a therapeuticallyeffective amount of drug may be at least 0.1 μg/day, 0.2 μg/day, 0.3μg/day, 0.4 μg/day, 0.5 μg/day, 0.6 μg/day, 0.7 μg/day, 0.8 μg/day, 0.9μg/day, 1 μg/day, 2 μg/day, 3 μg/day, 4 μg/day, 5 μg/day, 6 μg/day, 7μg/day, 8 μg/day, 9 μg/day, 10 μg/day, 15 μg/day, 20 μg/day, 25 μg/day,30 μg/day, 35 μg/day, 40 μg/day, 45 μg/day, 50 μg/day, 55 μg/day, 60μg/day, 65 μg/day, 70 μg/day, 75 μg/day, 80 μg/day, 85 μg/day, 90μg/day, 95 μg/day, 100 μg/day, 110 μg/day, 120 μg/day, 130 μg/day, 140μg/day, 150 μg/day, 160 μg/day, 170 μg/day, 180 μg/day, 190 μg/day, 200μg/day, 210 μg/day, 220 μg/day, 230 μg/day, 240 μg/day, 250 μg/day, 260μg/day, 270 μg/day, 280 μg/day, 290 μg/day, 300 μg/day, 310 μg/day, 320μg/day, 330 μg/day, 340 μg/day, 350 μg/day, 360 μg/day, 370 μg/day, 380μg/day, 390 μg/day, 400 μg/day, 410 μg/day, 420 μg/day, 430 μg/day, 440μg/day, 450 μg/day, 460 μg/day, 470 μg/day, 480 μg/day, 490 μg/day, 500μg/day, 510 μg/day, 520 μg/day, 530 μg/day, 540 μg/day, 550 μg/day, 560μg/day, 570 μg/day, 580 μg/day, 590 μg/day, 600 μg/day, 610 μg/day, 620μg/day, 630 μg/day, 640 μg/day, 650 μg/day, 660 μg/day, 670 μg/day, 680μg/day, 690 μg/day, 700 μg/day, 710 μg/day, 720 μg/day, 730 μg/day, 740μg/day, 750 μg/day, 760 μg/day, 770 μg/day, 780 μg/day, 790 μg/day, 800μg/day, 810 μg/day, 820 μg/day, 830 μg/day, 840 μg/day, 850 μg/day, 860μg/day, 870 μg/day, 880 μg/day, 890 μg/day, 900 μg/day, 910 μg/day, 920μg/day, 930 μg/day, 940 μg/day, 950 μg/day, 960 μg/day, 970 μg/day, 980μg/day, 990 μg/day, 1000 μg/day or greater. It should be understood thata therapeutically effective amount of drug may vary based on the drugand/or the disease to be treated, and may be determined empirically.

In various aspects, the implant may result in cumulative release of thetherapeutically active agent from the implant into the target tissue. Insome cases, the cumulative release of bicalutamide from the implant invitro may be at least 100 μg on day 1. In some cases, the cumulativerelease of bicalutamide from the implant in vitro may be at least 1,500μg on day 50. In some cases, the cumulative release of bicalutamide fromthe implant in vitro may be at least 2,000 μg on day 100. In some cases,at least 50% of the total amount of bicalutamide present within theimplant at the time of implantation remains in the polymer matrix at 100days post-implantation.

In various aspects of the disclosure, the implant may be configured toremain within the target tissue for a period of time. In some cases, theimplant may be configured to remain within the target tissue for longperiods of time (e.g., months to years) or indefinitely (e.g., may neverbe removed). For example, after the implant has delivered all of thetherapeutically active agent contained therein to the subject, theimplant (devoid of the therapeutically active agent) may remain withinthe target tissue. In some cases, if additional treatment is needed, oneor more additional implants may be delivered to the target tissue(without removing the initial implant). In some cases, the implant maybe composed of a non-biodegradable and/or non-resorbable polymermaterial such that the polymer material remains substantially intactwithin the target tissue for long periods of time or indefinitely.

Advantageously, the implants of the disclosure are capable of deliveringa therapeutically effective amount of bicalutamide to the prostatetissue, or tissue adjacent or near the prostate, for extended periods oftime (e.g., at least 6 months). Additionally, the implants of thedisclosure are capable of delivering a high concentration ofbicalutamide locally to the prostate, while maintaining low systemicconcentrations of bicalutamide. In some cases, the implants of thedisclosure may reduce or prevent toxicity due to high systemicconcentrations of bicalutamide.

In various aspects, a total dose of bicalutamide administered to thesubject by an implant of the disclosure is less than a total dose ofbicalutamide when administered to a subject by systemic (e.g., oral)administration. Standard oral dosing regimens of bicalutamide include150 mg/day bicalutamide monotherapy for early stage prostate cancer, and50 mg/day in combination with other therapies for advanced prostatecancers. Advantageously, the implants of the disclosure provide foradministration of lower total doses of bicalutamide relative to oraldosing regimens. In some cases, the total amount of bicalutamideadministered to a subject is less than 100 mg over a 6 month period.

In various aspects, implanting a drug implant of the disclosure into theprostate or tissue adjacent or near the prostate results in a bloodplasma concentration of bicalutamide that is substantially less than ablood plasma concentration of bicalutamide obtained when bicalutamide isadministered to a subject by systemic (e.g., oral) administration. Forexample, the steady state blood plasma concentration of R-enantiomer ofbicalutamide has been reported to be about 9 μg/ml. In some cases, animplanting an implant of the disclosure into the prostate or tissueadjacent or near the prostate results in a steady state blood plasmaconcentration of R-bicalutamide that is less than 9 μg/ml, for example,less than 5 μg/ml.

Kits

Further provided herein are kits. In some aspects, a kit may compriseone or more implants as described herein. For example, a kit may include1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 ormore than 20 implants. In some cases, the one or more implants maycomprise a therapeutically active agent contained therein. In somecases, each of the one or more implants may comprise the sametherapeutically active agent. In other cases, each of the one or moreimplants may comprise one or more different therapeutically activeagents.

In some aspects, a kit may comprise one or more surgical tools, such asa needle or forceps. In some aspects, a kit may be packaged in asterilized package. In some cases, the sterilized package comprises afoil. In some aspects, a kit may further comprise instructions forimplanting the implant into a tissue of a subject.

Certain Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. It is to be understoodthat the foregoing general description and the following detaileddescription are exemplary and explanatory only and are not restrictiveof any subject matter claimed.

In this application, the use of the singular includes the plural unlessspecifically stated otherwise. It must be noted that, as used in thespecification and the appended claims, the singular forms “a,” “an”, and“the” include plural referents unless the context clearly dictatesotherwise. In this application, the use of “or” means “and/or” unlessstated otherwise. Furthermore, use of the term “including” as well asother forms, such as “include”, “includes”, and “included”, is notlimiting.

As used herein, ranges and amounts can be expressed as “about” aparticular value or range. About also includes the exact amount. Hence“about 5 μL” means “about 5 μL” and also “5 μL.” Generally, the term“about” includes an amount that would be expected to be withinexperimental error, e.g., within 15%, 10%, or 5%.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Non-Limiting List of Exemplary Embodiments

In addition to the aspects and embodiments described and providedelsewhere in this disclosure, the following non-limiting list ofparticular embodiments are specifically contemplated.

-   -   1. An implant comprising:        -   a biocompatible, substantially non-biodegradable polymer            matrix; and        -   an anti-androgen dispersed throughout the polymer matrix.    -   2. An implant comprising:        -   a biocompatible polymer matrix; and        -   a therapeutically active agent dispersed throughout the            polymer matrix, wherein the implant delivers a            therapeutically effective amount of the therapeutically            active agent to a target tissue of a subject for at least 24            months when the implant is disposed in the target tissue of            the subject.    -   3. An implant comprising:        -   a biocompatible, substantially non-biodegradable polymer            matrix; and        -   an anti-androgen in crystalline form.    -   4. An implant comprising:        -   a biocompatible, substantially non-biodegradable polymer            matrix; and        -   an anti-androgen dispersed throughout the polymer matrix at            an amount from 10 to 70% w/w.    -   5. The implant of any one of embodiments 1-4, wherein the        implant, when disposed in the target tissue of the subject,        releases at least 0.1 μg/day of the therapeutically active agent        or the anti-androgen at 24 months after implantation.    -   6. The implant of any one of embodiments 1-5, wherein the        therapeutically active agent or the anti-androgen has a median        particle size of less than 10 microns.    -   7. The implant of any one of embodiments 1-6, wherein the        implant has a Shore A hardness of at least 30 durometer when        loaded with 60% w/w of a therapeutically active agent.    -   8. The implant of any one of embodiments 1-7, wherein at least        99% of the polymer matrix remains in the target tissue of the        subject after implantation for at least 600 days.    -   9. The implant of any one of embodiments 1-8, wherein the        implant is visible by ultrasound when disposed in the target        tissue of the subject.    -   10. The implant of any one of embodiments 1-9, wherein the        therapeutically active agent or the anti-androgen has a melting        temperature that is greater than a curing temperature of the        polymer matrix.    -   11. The implant of embodiment 10, wherein the melting        temperature is greater than 150° C.    -   12. The implant of any one of embodiments 1-11, wherein the        polymer matrix inhibits degradation of the therapeutically        active agent or the anti-androgen in the implant.    -   13. The implant of embodiment 12, wherein the polymer matrix        inhibits degradation of the therapeutically active agent or the        anti-androgen by an esterase or an amidase.    -   14. The implant of embodiment 12 or 13, wherein the degradation        is determined by measuring the amount of the therapeutically        active agent or the anti-androgen in an eluent after incubating        the implant containing the therapeutically active agent or the        anti-androgen in a solution comprising 1% SDS containing 0.05 N        NaOH for 8 hours at 37° C.    -   15. The implant of any one of embodiments 1-14, wherein the        implant is elongate.    -   16. The implant of any one of embodiments 1-15, wherein the        implant is cylindrical.    -   17. The implant of any one of embodiments 1-15, wherein the        implant is tubular.    -   18. The implant of any one of embodiments 1-17, wherein a        diameter of the implant is less than 1 mm.    -   19. The implant of any one of embodiments 1-18, wherein a        diameter of the implant is from 0.5 mm to 1.5 mm.    -   20. The implant of any one of embodiments 1-18, wherein a        diameter of the implant is from 0.7 mm to 1.3 mm.    -   21. The implant of any one of embodiments 1-18, wherein a        diameter of the implant is from 0.9 mm to 1.1 mm.    -   22. The implant of any one of embodiments 1-18, wherein a        diameter of the implant is about 1 mm.    -   23. The implant of any one of embodiments 1-22, wherein a length        the implant is less than 20 mm.    -   24. The implant of any one of embodiments 1-22, wherein a length        of the implant is from 5 mm to 25 mm.    -   25. The implant of any one of embodiments 1-22, wherein a length        of the implant is from 10 mm to 20 mm.    -   26. The implant of any one of embodiments 1-22, wherein a length        of the implant is from 12 mm to 18 mm.    -   27. The implant of any one of embodiments 1-22, wherein a length        of the implant is about 15 mm.    -   28. The implant of any one of embodiments 1-27, wherein the        implant further comprises a coating.    -   29. The implant of embodiment 28, wherein the coating partially        covers the implant.    -   30. The implant of embodiment 28, wherein the coating        substantially covers the implant.    -   31. The implant of embodiment 28, wherein the coating covers the        implant.    -   32. The implant of embodiment 2, wherein the therapeutically        active agent is an anti-androgen.    -   33. The implant of any one of embodiments 1-32, wherein the        therapeutically active agent or the anti-androgen is        bicalutamide.    -   34. The implant of any one of embodiments 1-33, wherein the        implant is sterile.    -   35. The implant of any one of embodiments 1-34, wherein the        implant is disposed in a sterilized package.    -   36. The implant of any one of embodiments 1-35, wherein the        polymer matrix is at least 95% cured, at least 96% cured, at        least 97% cured, at least 98% cured, at least 99% cured, or at        least 99.9% cured.    -   37. The implant of any one of embodiments 1-36, wherein the        polymer matrix comprises silicone.    -   38. The implant of embodiment 37, wherein the silicone is        Silbione® LSR D370 as manufactured by Elkem.    -   39. The implant of embodiment 37, wherein the silicone is DDU        4870 as manufactured by NuSil™.    -   40. The implant of any one of embodiments 1-39, wherein the        implant is configured to be implanted into prostate tissue of a        subject.    -   41. The implant of any one of embodiments 1-40, wherein the        implant lacks a metal.    -   42. A method of manufacturing an implant suitable for        implantation into the prostate of a subject, the method        comprising:        -   (a) mixing an amount of uncured biocompatible, substantially            non-biodegradable polymer with an amount of anti-androgen to            form a mixture;        -   (b) molding the mixture to create a molded mixture; and        -   (c) curing the molded mixture by heating the molded mixture            for a period of time.    -   43. The method of embodiment 42, wherein the amount of        anti-androgen is between 10% w/w and 70% w/w of the uncured        biocompatible, substantially non-biodegradable polymer.    -   44. The method of embodiment 42 or 43, wherein the anti-androgen        is bicalutamide.    -   45. The method of any one of embodiments 42-44, wherein the        biocompatible, substantially non-biodegradable polymer is a        silicone.    -   46. The method of embodiment 45, wherein the silicone is        Silbione® LSR D370 as manufactured by Elkem.    -   47. The method of embodiment 45, wherein the silicone is DDU        4870 as manufactured by NuSil™.    -   48. The method of any one of embodiments 42-47, wherein the        curing of (c) further comprises heating the molded mixture at a        temperature from about 150° C. to about 200° C. for 3 to 8        minutes.    -   49. The method of any one of embodiments 42-48, wherein the        mixture further comprises a solvent.    -   50. The method of embodiment 49, wherein the solvent is selected        from the group consisting of: pentane, dichloromethane,        tetrahydrofuran, heptane, toluene, and hexane.    -   51. The method of any one of embodiments 42-50, wherein the        mixture is molded by a transfer molding process.    -   52. The method of any one of embodiments 42-51, further        comprising, performing an analysis on the implant.    -   53. The method of embodiment 54, wherein the analysis is        selected from the group consisting of: differential scanning        calorimetry (DSC), deployment of implant in surrogate tissue,        elution testing, viscometry, high pressure liquid chromatography        (HPLC), and simulated in vivo stability assay.    -   54. A kit comprising:        -   a sterilized package comprising an implant according to any            one of embodiments 1-41 therein; and        -   instructions for implanting the implant into a target tissue            of a subject.    -   55. The kit of embodiment 54, wherein the implant is configured        for delivery into a human prostate, tissue adjacent the human        prostate, or both.    -   56. The kit of embodiment 54 or 55, wherein the sterilized        package is formed from a foil.    -   57. The kit of any one of embodiments 54-56, further comprising        one or more surgical tools for implanting the implant into the        target tissue of the subject.    -   58. The kit of embodiment 57, wherein the one or more surgical        tools comprises a needle, forceps, a trocar, or a stylet.    -   59. A method of treating a disease in a subject in need thereof,        comprising:    -   implanting an implant of any one of embodiments 1-41 into the        prostate of the subject, thereby treating the disease.    -   60. A method of treating a disease in a subject in need thereof,        comprising:        -   implanting a substantially non-biodegradable implant            comprising a biocompatible polymer matrix and an            anti-androgen drug dispersed throughout the biocompatible            polymer matrix into the prostate of the subject, thereby            treating the disease.    -   61. The method of embodiment 60, wherein the prostate comprises        prostate tissue, tissue adjacent the prostate tissue, or both.    -   62. The method of embodiment 60 or 61, wherein the disease is a        proliferative disease or disorder of the prostate (e.g.,        prostate cancer, benign prostatic hyperplasia).    -   63. The method of any one of embodiments 60-62, further        comprising disposing a distal end of an elongate tube in the        subject's prostate or tissue adjacent the prostate.    -   64. The method of embodiment 63, wherein a portion of the        elongate tube is disposed through a first portion of a grid such        that a first position of the elongate tube in the subject is        determined.    -   65. The method of embodiment 63 or 64, wherein the elongate tube        is a needle or a catheter.    -   66. The method of embodiment 65, wherein a trocar is disposed        within a lumen of the elongate tube.    -   67. The method of embodiment 66, further comprising removing the        trocar from the lumen of the elongate tube.    -   68. The method of embodiment 67, further comprising, after        removing the trocar from the lumen of the elongate tube,        positioning the implant within the lumen of the elongate tube.    -   69. The method of embodiment 68, further comprising pushing a        stylet through the lumen of the elongate tube, thereby        displacing the implant to the distal end of the elongate tube.    -   70. The method of embodiment 69, further comprising displacing        the elongate tube away from the subject such the implant remains        within the subject.    -   71. The method of embodiment 70, wherein the stylet is disposed        in a portion of the lumen of the elongate tube, a distal end of        the stylet adjacent the implant such that the implant remains        within the subject.    -   72. The method of any one of embodiments 60-71, wherein a        portion of a second elongate tube is disposed through a second        portion of the grid such that a position of the second elongate        tube in the subject is determined.

EXAMPLES Example 1. Methods for Making Implants

Manufacture of the implant included two main steps: formulation of theactive pharmaceutical ingredient (API) (e.g., bicalutamide) with anelastomer (e.g., heat cured silicone) to ensure uniform mixing of theAPI within the polymer matrix, and molding of the implants to ensure theproduct can be deployed to the organ as intended.

Formulation

The implant formulation included medical grade silicone as an excipientmixed with the API. A solvent was used for reducing the viscosity of thesilicone, if needed, to incorporate the desired API loading.

The 60% w/w bicalutamide formulation was made using a centrifugal mixer(FlackTek DAC400-VAC). The required amount of silicone Part A and Part Bwere added to the mixing cup and an equal weight of a solvent (thatdissolves silicone; e.g., pentane) was added. The silicone and solventwere speed-mixed until the viscosity of the silicone was reduced suchthat it flowed. The API powder was then incorporated into the mixing cupand speed-mixed until a visibly smooth mixture was obtained with no dryAPI spots. The solvent was then removed under vacuum leaving a paste ofsilicone and API. Table 1 below shows the formulation for 60% w/wbicalutamide using Silbione® LSR D370 as the silicone and pentane as asolvent for a 10-gram mix. Table 2 below lists a set of solvent removalparameters which can be repeated until the desired amount of solvent isremoved as confirmed by weight.

Other methods to achieve the same mix uniformity that are solvent-lessmay be used, such as shear mixing. Other solvents (e.g.,dichloromethane, tetrahydrofuran, hexane, pentane, heptane, toluene, andthe like) that aid in reduction of viscosity and dissolve silicone mayalso be used for formulation.

TABLE 1 Example Formulation Composition 60% w/w Bicalutamide ComponentWeight Added (g) Silbione ® LSR D370 Part A 2 Silbione ® LSR D370 Part B2 Solvent 4 Bicalutamide Milled Powder 6

TABLE 2 Example Solvent Removal Conditions Solvent Speed Time VacuumRemoval Cycle Step (RPM) (min) (psi) 1 1 950 1.8 9.0 2 950 0.3 14.7 31450 1.8 3.9 2 1 1950 2.8 3.9 2 1950 2.8 3.9 3 1950 2.8 3.9 4 1950 2.83.9 3 1 800 2.8 0.14 2 2400 0.3 0.14 3 950 2.8 0.14

Molding

Implant rods were made using an aluminum mold via a transfer moldingprocess. The molds were assembled, and a pre-weighed amount of theformulation was injected into the mold. Post-formulation injection, therods were cured for a predetermined time (3 to 8 minutes) at a certaintemperature (150 to 200° C.) based on the silicone supplier'srecommendations for curing. Post-curing, the mold was cooled, and therods were de-molded for characterization. FIG. 1 depicts an example of amolded implant according to Example 1.

Example 2. Characterization of Bicalutamide Containing Formulation andImplants

Various analytical techniques were used for characterization of theformulation and molded implants. Differential Scanning calorimetry (DSC)was used to determine the rate of curing of the implants and to confirmthat crystalline properties of the drug were not impacted. Deployment ofimplant in cow tongue was used to assess adequate deployment of theimplant due to its tissue properties which are comparable to theprostate. The method for deployment is described. Elution Testing wasused to assess the rate of elution of drug from the implant. Aviscometer was used to assess the viscosity and curing profile for theformulation to confirm that process parameters used are capable ofmolding cured rods. High Pressure Liquid Chromatography (HPLC) was usedto confirm content uniformity and assess impurities in the drugformulation and molded rods. Simulated in vivo stability assay was usedto assess the ability of degradants to penetrate the implant.

Differential Scanning calorimetry (DSC)

Samples were run on a TA Instruments Model Q2000 (V24.11 Build 124) DSCequipped with a nitrogen flow sample chamber. Samples were prepared byloading ˜5-15 mg of material into a hermetically sealed aluminum Tzeropan. The samples were placed on the DSC sampler and run under a nitrogenpurge (50 mL/min) at a rate of 10° C./min from 20° C. to 220° C. FIGS.2A-2F show a set of DSC thermograms that were generated duringdevelopment. A comparison of the thermogram of uncured silicone (FIG.2A) to an in-process formulation mix (FIG. 2C) and the molded rod (FIGS.2B and 2D) shows that the molded rods were fully cured and that the APIwas mixed into the formulation. A comparison of the thermogram for APIalone (FIG. 2E) and the molded rods at 45% w/w API (FIG. 2F) and 60% w/wAPI (FIG. 2D) showed no change in the melting range for the API (191 to193° C.) indicating that the crystalline structure of the API was likelynot altered during formulation and molding.

Implant Deployment

The drug implant was deployed into the prostate of dogs. To date, twopre-clinical studies in dogs have been performed and the data from thesestudies has shown that the implant can be successfully implanted in theprostate and remains within the prostate for at least 8 weeks (FIGS.3A-3C).

Elution Testing

Elution testing was performed to analyze the in vitro performance of themolded implant. Implants were placed in a 1% w/w sodium lauryl sulfate(SDS) solution and the elution media was replaced at regular intervals.The eluent of API was quantitated at each timepoint via UV/VisSpectroscopy or HPLC. A comparison of elution curves for a 30% w/w, 45%w/w, and 60% w/w bicalutamide formulation along with the predictedprofile out to −2 years is shown in FIGS. 4A-4C.

FIG. 4D depicts the cumulative release (μg/day) of bicalutamide from animplant containing 60% w/w bicalutamide in an in vitro model. FIG. 4Edepicts the release rate profile of bicalutamide from an implantcontaining 60% w/w bicalutamide in an in vitro model. FIG. 4F depicts apredicted cumulative release (ug/day) profile of an implant containing60% w/w bicalutamide demonstrating that there is enough bicalutamideloaded within the implant to provide a therapeutically effective dose ofdrug for 2 years. The dotted line indicates the total amount of drugloaded in the implant (˜8.4 mg).

FIG. 4G depicts the impact of age, storage conditions, and sterilizationon the cumulative release profiles of implants containing 60% w/wbicalutamide in an in vitro model. FIG. 4G demonstrates that differentstorage conditions, sterilization techniques, and age of the implantshas no impact on the cumulative release profiles of these implants in anin vitro model. FIG. 4H depicts the release rate of bicalutamide fromthese implants, again demonstrating no effect from different storageconditions, sterilization techniques, or age of the implants in an invitro model.

Simulated In Vivo Stability Assay

Simulated in vivo stability was performed to analyze the in vivostability of active agent within the implant. Implants containing 0%w/w, 30% w/w, 45% w/w, and 60% w/w bicalutamide were placed in a 1% SDSsolution containing 0.05 N NaOH (a degradant known to degradebicalutamide) for ˜8 hours at 37° C. Experimental controls included 0%w/w, 30% w/w, 45% w/w, and 60% w/w bicalutamide implants in 1% SDSwithout NaOH, as well as bicalutamide solution in 1% SDS with andwithout NaOH. Elution media and extracted bicalutamide from the implantswere analyzed using reversed phase high-pressure liquid chromatography(RP-HPLC). Results demonstrated that bicalutamide eluent in all samplescontaining NaOH, including bicalutamide solution, exhibited degradation(25% to 40% by area) (see FIG. 5). In contrast, no degradation peakswere observed for the extracted samples. Thus, the implant preventedNaOH to penetrate the device thereby protecting the bicalutamide withinthe implant from degradation.

Example 3. Analysis of a Drug Implant of the Disclosure Implanted intothe Prostate of Canines

In this study, three canines, at least fifteen months old, wereemployed. Each canine received two active implant devices containing 60%by weight of bicalutamide (˜8.4 mg)/Silbione Biomedical LSR D370silicone in a 15 mm long by 0.95 mm diameter rod. An 18-gaugebrachytherapy needle (OD 1.27 mm) was used for device implantation.Clinical observations and body weight were recorded. Blood was collectat frequent intervals for determination of plasma bicalutamideconcentrations and for clinical chemistry evaluation. After 55 days ofobservation, animals were euthanized and gross necropsy conducted,implanted devices were retrieved, and tissues (including prostate) werecollected for histopathological examination and bicalutamidequantitation.

Live Animal Component

During surgical implantation, a single device was placed into each lobeof the prostate without complication. Placement of devices was confirmedby transrectal ultrasound during implantation and 1, 7, 14, and 28 dayspost-implantation. Mild to moderate swelling around the surgicalincision site was observed in all three study animals, which wasresolved with anti-inflammatory (carprofen) treatment. Blood wascollected for clinical chemistry evaluation and bicalutamidequantitation. During the 55 days of observation, study animals exhibitedno signs of distress or adverse effects from the test devices.

Gross Necropsy and Histopathology Interpretation

55 days post-implantation, study animals were euthanized and underwentgross necropsy. No test device related pathology was noted duringnecropsy. Organs were sampled for histopathological evaluation andbicalutamide quantitation. Prostate glands were trimmed and cut in threesection perpendicular to the urethra: a cranial (rostral) section, a 3-5mm transverse section, and a caudal section. From the rostral piece, two5 mm punch biopsies were obtained surrounding the implant and the restof the rostral and caudal section were divided in 4 sections each andsent for bicalutamide quantitation. The transverse piece in its entiretywas sent for histopathological evaluation.

Histopathological evaluation found no device associated lesions innon-prostate tissues. Minimal kidney mineralization was observed butconsidered consistent with background findings in study canines.Prostates, testes, and epididymis were found to be mature and exhibitedno device-related pathology. Device tracts were not visible, nor was anyfibrotic encapsulation. Mild intergland fibrosis and lymphocyticinfiltration was observed in some animals but deemed consistent withpurpose-bred study canines.

Plasma Drug Quantification

Plasma total, R-, and S-bicalutamide levels were comparable across allthree study animals, peaking between 12 and 24 ng/mL (FIGS. 6A and 6B).Steady state was reached roughly by day 4 with average median levels of13.2±1.7, 9.1±1.3, and 5.0±0.5 through day 55 for total, R-, andS-bicalutamide, respectively. The ratio of R- to S-bicalutamide wasroughly 2:1. Note that the plasma levels as shown in FIGS. 6A and 6B arein micrograms for the oral dose while the scale is in ng/mL for thedevice plasma levels.

Solid Tissue Drug Quantification

Bicalutamide was quantified in major organs and prostate associatedtissues harvested during necropsy. Bicalutamide levels were highest inorgans of elimination (liver and kidney), as well as tested and lung.Consistent with plasma findings, the ratio of R- to S-bicalutamide was˜2:1. Compared to plasma levels, average accumulation was only apparentin liver (47±16, 28±9, and 19±7 ng/g versus 13±2, 9±1, and 5±1 ng/g, fortotal, R- and S-bicalutamide, respectively) but was very low compared toprostate exposure.

Prostate Gland Drug Quantification

Quantitation of prostate bicalutamide found whole gland levels of total,R-, and S-bicalutamide to be 172±21, 86±10, and 87±11 ng/g,respectively. Punch biopsies 5 mm in diameter surrounding deviceimplants resulted in an average total, R-, and S-bicalutamide of1426±501, 698±242, and 727±259 ng/g, respectively (FIGS. 7A and 7B).Unlike plasma and other organs, the ratio of R- and S-bicalutamide inprostate was roughly 1:1. As seen in FIG. 8, the R-bicalutamide levelswere higher surrounding the implant (red numbers in circles) withaverages per quadrant (black numbers) demonstrating elution throughoutthe prostate.

Study Summary

The study sought to evaluate safety, toxicity, and bicalutamide tissuedistribution in canines when two 60% bicalutamide by weight devices wereimplanted into the prostate. No significant safety or toxicity findingswere observed during the live animal portion of the study. Consistently,gross and histopathological analysis of major organs andprostate-associated tissues found no lesions contributable to the studydevices, including foreign body response, which might impairbicalutamide delivery to the prostate. Comparison of bicalutamide levelsin plasma, organs, and prostate demonstrated significantly greater local(e.g., prostate) exposure was achieved. Whole prostate gland levelsachieved for the active R-bicalutamide isomer (84.6±10.1 ng/g or196.6±23.5 nM) is sufficient to inhibit the androgen receptor incell-free androgen binding studies (IC₅₀˜190 nM). Prostate tissue within˜5 mm of the device reached R-bicalutamide levels (698±242 ng/g or1623±562 nM) demonstrated to inhibit prostate cancer cells (IC₅₀˜1000nM). The even distribution of R- and S-bicalutamide (˜1:1) found in theprostate supports device delivery, rather than systemic recirculation,as isomeric formulation in the device is ˜1:1, while hepatic metabolismresults in a systemic ratio of 2:1 in this canine model.

The prostate was divided into three pieces to enable a more thoroughassessment of bicalutamide delivery, while preserving the ability toevaluate histopathology. Although limited to a relatively thintransverse section of the prostate, this centrally positioned slicewould be in contact or in close proximity to implanted devices and thusenable histopathological analysis of device and delivered bicalutamideimpact on tissue. Further, having sent the center transverse section ofthe prostate for histopathology, its contribution to whole glandprostate bicalutamide level was not included. This likely results in anunderestimation of whole gland bicalutamide as this device proximalportion likely had higher average levels than other portions of thegland (e.g., caudal piece), which were more distant from devices.

While preferred embodiments of the present disclosure have been shownand described herein, it will be obvious to those skilled in the artthat such embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the disclosure. It should beunderstood that various alternatives to the embodiments of thedisclosure described herein may be employed in practicing thedisclosure. It is intended that the following claims define the scope ofthe disclosure and that methods and structures within the scope of theseclaims and their equivalents be covered thereby.

1. A drug/polymer composite prostate implant comprising: a siliconerubber matrix having a Shore A hardness of at least 30 durometer; andbicalutamide having a D90 of less than 15 microns dispersed in thesilicone matrix at an amount of at least 30% w/w, wherein the prostateimplant releases between 1.2 μg/day and 10 μg/day of the bicalutamide at2-years after implantation in a subject.
 2. (canceled)
 3. The prostateimplant of claim 1, wherein the bicalutamide is in solid form.
 4. Theprostate implant of claim 3, wherein the solid form has a medianparticle size of less than 10 microns.
 5. (canceled)
 6. (canceled) 7.(canceled)
 8. The prostate implant of claim 1, wherein the silicone hasa curing temperature less than a melting point of bicalutamide.
 9. Theprostate implant of claim 1, wherein at least 50% of the bicalutamideremains in the silicone matrix after 100 days of implantation.
 10. Theprostate implant of claim 1, wherein the silicone rubber matrix is aliquid silicone rubber.
 11. (canceled)
 12. (canceled)
 13. The prostateimplant of claim 1, wherein a volume of the prostate implant is at least10 mm³.
 14. The prostate implant of claim 1, wherein a length of theprostate implant is from 1 mm to 30 mm.
 15. The prostate implant ofclaim 1, wherein a length of the prostate implant is from 5 mm to 25 mm.16. The prostate implant of claim 1, wherein a diameter of the prostateimplant is from 0.1 mm to 1.5 mm.
 17. The prostate implant of claim 1,wherein the bicalutamide is dispersed in the polymer matrix at an amountof at least 40% w/w.
 18. The prostate implant of claim 1, wherein atleast 50% of an outer surface of the polymer matrix is uncoated.
 19. Theprostate implant of claim 1, wherein the prostate implant is deliverableusing a canula of a needle.
 20. The prostate implant of claim 1,consisting essentially of the polymer matrix and the bicalutamidedispersed in the polymer matrix.
 21. The prostate implant of claim 1,wherein the bicalutamide is in crystalline form.
 22. The prostateimplant of claim 1, wherein the bicalutamide is in solid, amorphousform.
 23. The prostate implant of claim 1, wherein the outer surface ofthe prostate implant polymer matrix is coated.
 24. (canceled)